Two alpha(2)-adrenergic receptor subtypes, alpha(2A) and alpha(2C), inhibit transmitter release in the brain of gene-targeted mice

alpha(2)-Adrenergic receptors play an essential role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the CNS. However, the role of each of the three highly homologous alpha(2)-adrenergic receptor subtypes (alpha(2A), alpha(2B), alpha(2C)) in this process has not been determined unequivocally. To address this question, the regulation of norepinephrine and dopamine release was studied in mice carrying deletions in the genes encoding the three alpha(2)-adrenergic receptor subtypes. Autoradiography and radioligand binding studies showed that alpha(2)-receptor density in alpha(2A)-deficient brains was decreased to 9 +/- 1% of the respective wild-type value, whereas alpha(2)-receptor levels were reduced to 83 +/- 4% in alpha(2C)-deficient mice. These results indicate that approximately 90% of mouse brain alpha(2)-receptors belong to the alpha(2A) subtype and 10% are alpha(2C)-receptors. In isolated brain cortex slices from wild-type mice a non-subtype-selective alpha(2)-receptor agonist inhibited release of [(3)H]norepinephrine by maximally 96%. Similarly, release of [(3)H]dopamine from isolated basal ganglion slices was inhibited by 76% by an alpha(2)-receptor agonist. In alpha(2A)-receptor-deficient mice, the inhibitory effect of the alpha(2)-receptor agonist on norepinephrine and dopamine release was significantly reduced but not abolished. Only in tissues from mice lacking both alpha(2A)- and alpha(2C)-receptors was no alpha(2)-receptor agonist effect on transmitter release observed. The time course of onset of presynaptic inhibition of norepinephrine release was much faster for the alpha(2A)-receptor than for the alpha(2C)-subtype. After prolonged stimulation with norepinephrine, presynaptic alpha(2C)-adrenergic receptors were desensitized. From these data we suggest that two functionally distinct alpha(2)-adrenergic receptor subtypes, alpha(2A) and alpha(2C), operate as presynaptic inhibitory receptors regulating neurotransmitter release in the mouse CNS

Two alpha(2)-adrenergic receptor subtypes, alpha(2A) and alpha(2C), inhibit transmitter release in the brain of gene-targeted mice

alpha(2)-Adrenergic receptors play an essential role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the CNS. However, the role of each of the three highly homologous alpha(2)-adrenergic receptor subtypes (alpha(2A), alpha(2B), alpha(2C)) in this process has not been determined unequivocally. To address this question, the regulation of norepinephrine and dopamine release was studied in mice carrying deletions in the genes encoding the three alpha(2)-adrenergic receptor subtypes. Autoradiography and radioligand binding studies showed that alpha(2)-receptor density in alpha(2A)-deficient brains was decreased to 9 +/- 1% of the respective wild-type value, whereas alpha(2)-receptor levels were reduced to 83 +/- 4% in alpha(2C)-deficient mice. These results indicate that approximately 90% of mouse brain alpha(2)-receptors belong to the alpha(2A) subtype and 10% are alpha(2C)-receptors. In isolated brain cortex slices from wild-type mice a non-subtype-selective alpha(2)-receptor agonist inhibited release of [(3)H]norepinephrine by maximally 96%. Similarly, release of [(3)H]dopamine from isolated basal ganglion slices was inhibited by 76% by an alpha(2)-receptor agonist. In alpha(2A)-receptor-deficient mice, the inhibitory effect of the alpha(2)-receptor agonist on norepinephrine and dopamine release was significantly reduced but not abolished. Only in tissues from mice lacking both alpha(2A)- and alpha(2C)-receptors was no alpha(2)-receptor agonist effect on transmitter release observed. The time course of onset of presynaptic inhibition of norepinephrine release was much faster for the alpha(2A)-receptor than for the alpha(2C)-subtype. After prolonged stimulation with norepinephrine, presynaptic alpha(2C)-adrenergic receptors were desensitized. From these data we suggest that two functionally distinct alpha(2)-adrenergic receptor subtypes, alpha(2A) and alpha(2C), operate as presynaptic inhibitory receptors regulating neurotransmitter release in the mouse CNS

Diffusion Monte Carlo calculations for the ground states of atoms and ions in neutron star magnetic fields

The diffusion quantum Monte Carlo method is extended to solve the old theoretical physics problem of many-electron atoms and ions in intense magnetic fields. The feature of our approach is the use of adiabatic approximation wave functions augmented by a Jastrow factor as guiding functions to initialize the quantum Monte Carlo prodecure. We calcula te the ground state energies of atoms and ions with nuclear charges from Z= 2, 3, 4, ..., 26 for magnetic field strengths relevant for neutron stars.Comment: 6 pages, 1 figure, proceedings of the "9th International Conference on Path Integrals - New Trends and Perspectives", Max-Planck-Institut fur Physik komplexer Systeme, Dresden, Germany, September 23 - 28, 2007, to be published as a book by World Scientific, Singapore (2008

Human Computation and Convergence

Humans are the most effective integrators and producers of information, directly and through the use of information-processing inventions. As these inventions become increasingly sophisticated, the substantive role of humans in processing information will tend toward capabilities that derive from our most complex cognitive processes, e.g., abstraction, creativity, and applied world knowledge. Through the advancement of human computation - methods that leverage the respective strengths of humans and machines in distributed information-processing systems - formerly discrete processes will combine synergistically into increasingly integrated and complex information processing systems. These new, collective systems will exhibit an unprecedented degree of predictive accuracy in modeling physical and techno-social processes, and may ultimately coalesce into a single unified predictive organism, with the capacity to address societies most wicked problems and achieve planetary homeostasis.Comment: Pre-publication draft of chapter. 24 pages, 3 figures; added references to page 1 and 3, and corrected typ

Respiratory Paradoxical Adverse Drug Reactions Associated with Acetylcysteine and Carbocysteine Systemic Use in Paediatric Patients: A National Survey

OBJECTIVE: To report pediatric cases of paradoxical respiratory adverse drug reactions (ADRs) after exposure to oral mucolytic drugs (carbocysteine, acetylcysteine) that led to the withdrawal of licenses for these drugs for infants in France and then Italy. DESIGN: The study followed the recommendations of the European guidelines of pharmacovigilance for medicines used in the paediatric population. SETTING: Cases voluntarily reported by physicians from 1989 to 2008 were identified in the national French pharmacovigilance public database and in drug company databases. PATIENTS: The definition of paradoxical respiratory ADRs was based on the literature. Exposure to mucolytic drugs was arbitrarily defined as having received mucolytic drugs for at least 2 days (>200 mg) and at least until the day before the first signs of the suspected ADR. RESULTS: The non-exclusive paradoxical respiratory ADRs reported in 59 paediatric patients (median age 5 months, range 3 weeks to 34 months, 98% younger than 2 years old) were increased bronchorrhea or mucus vomiting (n = 27), worsening of respiratory distress during respiratory tract infection (n = 35), dyspnoea (n = 18), cough aggravation or prolongation (n = 11), and bronchospasm (n = 1). Fifty-one (86%) children required hospitalization or extended hospitalization because of the ADR; one patient died of pulmonary oedema after mucus vomiting. CONCLUSION: Parents, physicians, pharmacists, and drug regulatory agencies should know that the benefit risk ratio of mucolytic drugs is at least null and most probably negative in infants according to available evidence

Peanut‐induced anaphylaxis in children and adolescents: Data from the European Anaphylaxis Registry

Background Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%-1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents. Methods Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre. Results 3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004). Conclusions The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition